The robustness and breadth of T cell-mediated immunity has been suggested to influence the natural course of hepatitis C virus (HCV) infection by directly and indirectly controlling viral replication, the level of viremia, and progression to the chronic state. Hence, the development of vaccines and immunotherapeutic products that stimulate potent T cell immune responses in naive as well as infected individuals is of major importance. Globelmmune has developed a vaccine and immunotherapy platform based on the use of whole, heat-inactivated, recombinant S. cerevisiae yeast as a delivery vehicle. Globelmmune's products, termed Tarmogens(tm) (Targeted molecular immunogens), have been shown to elicit cellular immune responses against target cells expressing a variety of viral and cancer antigens, in a variety of animal species, and to do so in an antigen-specific, CD8+ CTL-mediated fashion. Two major advantages of using Tarmogens are that they bind to a variety of pattern recognition receptors including multiple Toll-like receptors on dendritic cells and do not appear to be neutralized upon repeated administration. Globelmmune's 1st generation products, GI-4000, targeting mutant human K-Ras, and GI-5005, targeting HCV NS3 and Core, are currently being investigated in phase 1 clinical trials in patients with pancreas, colorectal and lung cancer and in chronically HCV-infected individuals, respectively. The overall goals of the proposed project are: (1) to produce 2nd generation Tarmogens that target a broader array of HCV antigens; (2) to establish cGMP manufacturing and validation protocols; (3) to perform critical and thorough preclinical safety and immunogenicity testing in mice; (4) to show that the new Tarmogens can stimulate human HCV-specific T cells in vitro; and (5) to perform, following consultation with the FDA, GLP toxicity studies in anticipation of initiation of clinical trials in healthy, non-HCV-infected individuals as well as in chronically HCV-infected patients. Lay Summary: More than 4 million persons in the U.S. are currently infected with hepatitis C virus (HCV) and millions are at risk of infection. There are no vaccines and available drug therapies are toxic and are not effective in many individuals. Globelmmune has identified a novel use of ordinary Baker's yeast to prevent and treat HCV infection and is currently testing a product in infected individuals. The goal of this project is to prepare 2nd generation products that will ultimately be tested in humans to prevent and treat HCV infection. [unreadable] [unreadable] [unreadable] [unreadable]